The hypocretins (Hcrts), also known as orexins, are two hypothalamic neuropeptides, discovered by the applicant, with key functions in arousal maintenance, acute stress and brain reward function (de Lecea et al., 1998;de Lecea and Sutcliffe, 2005). The overarching goal of the original proposal is to determine the role of the hypocretins in reinstatement of drug seeking behavior by using genetic and pharmacological tools. In particular, we planned to determine whether intracerebroventricular infusions of Hcrt-1 reinstated an extinguished cocaine seeking behavior in mice, and whether Hcrt1 antagonists could block cue or stress induced cocaine seeking. During the past three years, we have made tremendous progress in these aims, and in parallel, we have implemented the newly developed optogenetic methods in freely moving mice. Optogenetic methods allow manipulation of genetically defined groups of neurons with millisecond temporal resolution (Boyden et al., 2005). Under this supplement, we plan to expand our experiments to determine whether optogenetic stimulation of Hcrt neurons can reinstate cocaine seeking in mice. This goal falls into the priorities of the OppNet ARRA mechanism: Development of novel animal models of behavior or translation of existing models toward new problems. If successful, these experiments will provide causal relationships between activation of endogenous Hcrt neurons and reinstatement of drug seeking. The experiments proposed in this supplement will also set the groundwork to determine the minimal requirements to trigger relapse. Expansion of original hypothesis with optogenetics is a major step forward in our understanding of the mechanisms underlying self-administration and reinstatement of drug seeking, and may lead to potential treatments to prevent cravings and relapse. PUBLIC HEALTH RELEVANCE: Substance abuse is a major health concern, most notably because in spite of numerous efforts most addicts have cravings during long periods and eventually relapse. This application will use state-of-the-art technology to extend the hypothesis in the parent grant, that neuropeptide Hypocretin has an important role in relapse of drug seeking. In particular, we will use optogenetics, a method that stimulates genetically identified neurons with unprecedented temporal resolution, to establish a causal role between endogenous release of neuropeptide Hcrt and relapse of cocaine seeking. This demonstration may lead to future treatments to prevent relapse.